The overall objecfive of this project is to utilize genomic and genetic data obtained from human pancreatic cancer (PCa) samples and observations from mouse models of PCa to understand the genetic events that drive tumor progression and treatment resistance in this disease. These mouse models include recent observations about PCa genesis and novel Sleeping Beauty (SB) transposon-based, forward genefic screens for PCa. The human PCa samples have been obtained from a novel collection via a rapid autopsy program developed by co-leader Christine lacobuzio-Donahue and fine needle aspirations (FNA) obtained by members of this SPORE group. These samples are being profiled for genetic alterations and markers identified in the mouse models. This has provided insight into the genetic drivers of PCa development and candidates for causing speciflc PCa phenotypes such as metastatic spread. We will discover novel genefic correlates of tumor progression, metastasis, and outcome using gene copy number, mRNA levels, sequence alterations and immunohistochemistry. Functional validation of novel targets will take place using gene overexpression or shRNA gene knockdown in PCa cell lines, xenografts, and mouse transgenic models. Moreover, these mulfi-dimensional data will be the basis for investigafing pharmacological suppression of pathways that cooperate to drive PCa development and progression. Our inifial focus is on a novel regulator of the TGF-beta and other pathways called Usp9x, and PTEN-regulated pathways. These experiments will set the stage for new clinical trials for PCa to be carried out during the next project period.